JP5826933B2 - 水溶性カンプトテシン誘導体、医薬組成物およびそれらの使用 - Google Patents
水溶性カンプトテシン誘導体、医薬組成物およびそれらの使用 Download PDFInfo
- Publication number
- JP5826933B2 JP5826933B2 JP2014521901A JP2014521901A JP5826933B2 JP 5826933 B2 JP5826933 B2 JP 5826933B2 JP 2014521901 A JP2014521901 A JP 2014521901A JP 2014521901 A JP2014521901 A JP 2014521901A JP 5826933 B2 JP5826933 B2 JP 5826933B2
- Authority
- JP
- Japan
- Prior art keywords
- cancer
- formula
- cpt
- group
- substituted
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical class C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 title claims description 25
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 5
- 229940127093 camptothecin Drugs 0.000 claims description 95
- 150000001875 compounds Chemical class 0.000 claims description 54
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 claims description 46
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 claims description 43
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical compound CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 claims description 40
- 229910052739 hydrogen Inorganic materials 0.000 claims description 34
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 32
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical class O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 claims description 30
- 239000001257 hydrogen Substances 0.000 claims description 27
- 206010028980 Neoplasm Diseases 0.000 claims description 26
- 125000006239 protecting group Chemical group 0.000 claims description 24
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 claims description 23
- 229930024421 Adenine Natural products 0.000 claims description 23
- 229960000643 adenine Drugs 0.000 claims description 23
- 229940104302 cytosine Drugs 0.000 claims description 23
- 229940113082 thymine Drugs 0.000 claims description 20
- 239000002777 nucleoside Substances 0.000 claims description 19
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 18
- 201000011510 cancer Diseases 0.000 claims description 18
- 150000003833 nucleoside derivatives Chemical class 0.000 claims description 18
- 125000001072 heteroaryl group Chemical group 0.000 claims description 16
- 125000002950 monocyclic group Chemical group 0.000 claims description 15
- 229940035893 uracil Drugs 0.000 claims description 15
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical class [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 13
- 229910052760 oxygen Inorganic materials 0.000 claims description 13
- 125000003277 amino group Chemical group 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 12
- 239000002773 nucleotide Substances 0.000 claims description 12
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 11
- 125000004434 sulfur atom Chemical group 0.000 claims description 11
- HBJGQJWNMZDFKL-UHFFFAOYSA-N 2-chloro-7h-purin-6-amine Chemical class NC1=NC(Cl)=NC2=C1NC=N2 HBJGQJWNMZDFKL-UHFFFAOYSA-N 0.000 claims description 9
- MFEFTTYGMZOIKO-UHFFFAOYSA-N 5-azacytosine Chemical class NC1=NC=NC(=O)N1 MFEFTTYGMZOIKO-UHFFFAOYSA-N 0.000 claims description 9
- 125000002252 acyl group Chemical group 0.000 claims description 9
- 125000003118 aryl group Chemical group 0.000 claims description 9
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 9
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 8
- WKMPTBDYDNUJLF-UHFFFAOYSA-N 2-fluoroadenine Chemical class NC1=NC(F)=NC2=C1N=CN2 WKMPTBDYDNUJLF-UHFFFAOYSA-N 0.000 claims description 7
- 206010006187 Breast cancer Diseases 0.000 claims description 7
- 208000026310 Breast neoplasm Diseases 0.000 claims description 7
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical class FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 claims description 7
- 206010041067 Small cell lung cancer Diseases 0.000 claims description 7
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 208000029742 colonic neoplasm Diseases 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 7
- 229960002949 fluorouracil Drugs 0.000 claims description 7
- 150000002431 hydrogen Chemical group 0.000 claims description 7
- 208000000587 small cell lung carcinoma Diseases 0.000 claims description 7
- 206010009944 Colon cancer Diseases 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 6
- RLMOMHNXIWBGTF-UHFFFAOYSA-N diaminophosphinoamine Chemical compound NP(N)N RLMOMHNXIWBGTF-UHFFFAOYSA-N 0.000 claims description 4
- 239000003085 diluting agent Substances 0.000 claims description 4
- 239000002243 precursor Substances 0.000 claims description 4
- 239000000376 reactant Substances 0.000 claims description 4
- YFIDCUXYXQUPSM-UHFFFAOYSA-N 1,4,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol Chemical class OC1CN=CNC2=C1N=CN2 YFIDCUXYXQUPSM-UHFFFAOYSA-N 0.000 claims description 3
- 239000008280 blood Substances 0.000 claims description 3
- 210000004369 blood Anatomy 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 230000007062 hydrolysis Effects 0.000 claims description 3
- 238000006460 hydrolysis reaction Methods 0.000 claims description 3
- 208000032839 leukemia Diseases 0.000 claims description 3
- 201000001441 melanoma Diseases 0.000 claims description 3
- 230000003647 oxidation Effects 0.000 claims description 3
- 238000007254 oxidation reaction Methods 0.000 claims description 3
- 125000001424 substituent group Chemical group 0.000 claims description 3
- 208000003174 Brain Neoplasms Diseases 0.000 claims description 2
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 2
- 206010017993 Gastrointestinal neoplasms Diseases 0.000 claims description 2
- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 2
- 206010033128 Ovarian cancer Diseases 0.000 claims description 2
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 2
- 206010060862 Prostate cancer Diseases 0.000 claims description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 2
- 206010038389 Renal cancer Diseases 0.000 claims description 2
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 2
- 208000006593 Urologic Neoplasms Diseases 0.000 claims description 2
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 2
- 208000002495 Uterine Neoplasms Diseases 0.000 claims description 2
- 238000005915 ammonolysis reaction Methods 0.000 claims description 2
- 201000010881 cervical cancer Diseases 0.000 claims description 2
- 206010017758 gastric cancer Diseases 0.000 claims description 2
- 201000010982 kidney cancer Diseases 0.000 claims description 2
- 201000007270 liver cancer Diseases 0.000 claims description 2
- 208000014018 liver neoplasm Diseases 0.000 claims description 2
- 201000005202 lung cancer Diseases 0.000 claims description 2
- 208000020816 lung neoplasm Diseases 0.000 claims description 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 2
- 201000002528 pancreatic cancer Diseases 0.000 claims description 2
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 2
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 claims description 2
- 201000011549 stomach cancer Diseases 0.000 claims description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 2
- 206010046766 uterine cancer Diseases 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims 1
- 208000015181 infectious disease Diseases 0.000 claims 1
- 230000002458 infectious effect Effects 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 229940127073 nucleoside analogue Drugs 0.000 claims 1
- 125000004115 pentoxy group Chemical group [*]OC([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims 1
- -1 phosphoramidite ester Chemical class 0.000 description 25
- 229940002612 prodrug Drugs 0.000 description 18
- 239000000651 prodrug Substances 0.000 description 18
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 16
- 230000030833 cell death Effects 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 231100000673 dose–response relationship Toxicity 0.000 description 11
- 230000004962 physiological condition Effects 0.000 description 11
- 230000001093 anti-cancer Effects 0.000 description 10
- 150000002596 lactones Chemical group 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 238000006911 enzymatic reaction Methods 0.000 description 9
- 229910019142 PO4 Inorganic materials 0.000 description 8
- 239000002246 antineoplastic agent Substances 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- 239000010452 phosphate Substances 0.000 description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 8
- 102000011727 Caspases Human genes 0.000 description 7
- 108010076667 Caspases Proteins 0.000 description 7
- NYHBQMYGNKIUIF-UUOKFMHZSA-N Guanosine Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O NYHBQMYGNKIUIF-UUOKFMHZSA-N 0.000 description 7
- 239000004480 active ingredient Substances 0.000 description 7
- 230000022534 cell killing Effects 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 125000000524 functional group Chemical group 0.000 description 7
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 7
- XSCHRSMBECNVNS-UHFFFAOYSA-N quinoxaline Chemical compound N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 description 6
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 6
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 6
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 6
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 6
- 229960005420 etoposide Drugs 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 150000003573 thiols Chemical group 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N floxuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 description 5
- 125000003835 nucleoside group Chemical group 0.000 description 5
- FPVKHBSQESCIEP-UHFFFAOYSA-N (8S)-3-(2-deoxy-beta-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol Natural products C1C(O)C(CO)OC1N1C(NC=NCC2O)=C2N=C1 FPVKHBSQESCIEP-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- PTOAARAWEBMLNO-KVQBGUIXSA-N Cladribine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)O1 PTOAARAWEBMLNO-KVQBGUIXSA-N 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 4
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 4
- 230000004913 activation Effects 0.000 description 4
- 230000005775 apoptotic pathway Effects 0.000 description 4
- 238000013459 approach Methods 0.000 description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 4
- 229960002436 cladribine Drugs 0.000 description 4
- WDDPHFBMKLOVOX-AYQXTPAHSA-N clofarabine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1F WDDPHFBMKLOVOX-AYQXTPAHSA-N 0.000 description 4
- 229960000928 clofarabine Drugs 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 239000002502 liposome Substances 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 125000003729 nucleotide group Chemical group 0.000 description 4
- 239000002245 particle Substances 0.000 description 4
- 229960002340 pentostatin Drugs 0.000 description 4
- FPVKHBSQESCIEP-JQCXWYLXSA-N pentostatin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(N=CNC[C@H]2O)=C2N=C1 FPVKHBSQESCIEP-JQCXWYLXSA-N 0.000 description 4
- RDOWQLZANAYVLL-UHFFFAOYSA-N phenanthridine Chemical compound C1=CC=C2C3=CC=CC=C3C=NC2=C1 RDOWQLZANAYVLL-UHFFFAOYSA-N 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- HBZBAMXERPYTFS-SECBINFHSA-N (4S)-2-(6,7-dihydro-5H-pyrrolo[3,2-f][1,3]benzothiazol-2-yl)-4,5-dihydro-1,3-thiazole-4-carboxylic acid Chemical compound OC(=O)[C@H]1CSC(=N1)c1nc2cc3CCNc3cc2s1 HBZBAMXERPYTFS-SECBINFHSA-N 0.000 description 3
- UHDGCWIWMRVCDJ-UHFFFAOYSA-N 1-beta-D-Xylofuranosyl-NH-Cytosine Natural products O=C1N=C(N)C=CN1C1C(O)C(O)C(CO)O1 UHDGCWIWMRVCDJ-UHFFFAOYSA-N 0.000 description 3
- ASJSAQIRZKANQN-CRCLSJGQSA-N 2-deoxy-D-ribose Chemical group OC[C@@H](O)[C@@H](O)CC=O ASJSAQIRZKANQN-CRCLSJGQSA-N 0.000 description 3
- XAUDJQYHKZQPEU-KVQBGUIXSA-N 5-aza-2'-deoxycytidine Chemical compound O=C1N=C(N)N=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 XAUDJQYHKZQPEU-KVQBGUIXSA-N 0.000 description 3
- NMUSYJAQQFHJEW-KVTDHHQDSA-N 5-azacytidine Chemical compound O=C1N=C(N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NMUSYJAQQFHJEW-KVTDHHQDSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- DWRXFEITVBNRMK-UHFFFAOYSA-N Beta-D-1-Arabinofuranosylthymine Natural products O=C1NC(=O)C(C)=CN1C1C(O)C(O)C(CO)O1 DWRXFEITVBNRMK-UHFFFAOYSA-N 0.000 description 3
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 3
- 102000047934 Caspase-3/7 Human genes 0.000 description 3
- 108700037887 Caspase-3/7 Proteins 0.000 description 3
- MIKUYHXYGGJMLM-GIMIYPNGSA-N Crotonoside Natural products C1=NC2=C(N)NC(=O)N=C2N1[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O MIKUYHXYGGJMLM-GIMIYPNGSA-N 0.000 description 3
- UHDGCWIWMRVCDJ-PSQAKQOGSA-N Cytidine Natural products O=C1N=C(N)C=CN1[C@@H]1[C@@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-PSQAKQOGSA-N 0.000 description 3
- NYHBQMYGNKIUIF-UHFFFAOYSA-N D-guanosine Natural products C1=2NC(N)=NC(=O)C=2N=CN1C1OC(CO)C(O)C1O NYHBQMYGNKIUIF-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Natural products OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229960005305 adenosine Drugs 0.000 description 3
- 125000003342 alkenyl group Chemical group 0.000 description 3
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 description 3
- 229940041181 antineoplastic drug Drugs 0.000 description 3
- 229960002756 azacitidine Drugs 0.000 description 3
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 3
- IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- UHDGCWIWMRVCDJ-ZAKLUEHWSA-N cytidine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-ZAKLUEHWSA-N 0.000 description 3
- 229960003603 decitabine Drugs 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- 229960000961 floxuridine Drugs 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 229960005277 gemcitabine Drugs 0.000 description 3
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 3
- 229940029575 guanosine Drugs 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 150000002367 halogens Chemical class 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 229910052698 phosphorus Inorganic materials 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 230000002195 synergetic effect Effects 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 229940104230 thymidine Drugs 0.000 description 3
- 238000005292 vacuum distillation Methods 0.000 description 3
- BBVIDBNAYOIXOE-UHFFFAOYSA-N 1,2,4-oxadiazole Chemical compound C=1N=CON=1 BBVIDBNAYOIXOE-UHFFFAOYSA-N 0.000 description 2
- YGTAZGSLCXNBQL-UHFFFAOYSA-N 1,2,4-thiadiazole Chemical compound C=1N=CSN=1 YGTAZGSLCXNBQL-UHFFFAOYSA-N 0.000 description 2
- FKASFBLJDCHBNZ-UHFFFAOYSA-N 1,3,4-oxadiazole Chemical compound C1=NN=CO1 FKASFBLJDCHBNZ-UHFFFAOYSA-N 0.000 description 2
- PSTKRGSPZXXTFC-UHFFFAOYSA-N 1-methyl-1,3,5-triazinane-2,4-dione Chemical compound CN1CNC(=O)NC1=O PSTKRGSPZXXTFC-UHFFFAOYSA-N 0.000 description 2
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 2
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 2
- VLRSADZEDXVUPG-UHFFFAOYSA-N 2-naphthalen-1-ylpyridine Chemical compound N1=CC=CC=C1C1=CC=CC2=CC=CC=C12 VLRSADZEDXVUPG-UHFFFAOYSA-N 0.000 description 2
- VHMICKWLTGFITH-UHFFFAOYSA-N 2H-isoindole Chemical compound C1=CC=CC2=CNC=C21 VHMICKWLTGFITH-UHFFFAOYSA-N 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- UJOBWOGCFQCDNV-UHFFFAOYSA-N 9H-carbazole Chemical compound C1=CC=C2C3=CC=CC=C3NC2=C1 UJOBWOGCFQCDNV-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 2
- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 description 2
- 102000003915 DNA Topoisomerases Human genes 0.000 description 2
- 108090000323 DNA Topoisomerases Proteins 0.000 description 2
- 108090000371 Esterases Proteins 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 2
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical group [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 2
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- DRTQHJPVMGBUCF-XVFCMESISA-N Uridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-XVFCMESISA-N 0.000 description 2
- DZBUGLKDJFMEHC-UHFFFAOYSA-N acridine Chemical compound C1=CC=CC2=CC3=CC=CC=C3N=C21 DZBUGLKDJFMEHC-UHFFFAOYSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 125000004442 acylamino group Chemical group 0.000 description 2
- 230000006978 adaptation Effects 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 150000001408 amides Chemical group 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 210000001072 colon Anatomy 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 238000001647 drug administration Methods 0.000 description 2
- 238000009509 drug development Methods 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 235000003599 food sweetener Nutrition 0.000 description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 2
- 150000002390 heteroarenes Chemical class 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 2
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 2
- HOBCFUWDNJPFHB-UHFFFAOYSA-N indolizine Chemical compound C1=CC=CN2C=CC=C21 HOBCFUWDNJPFHB-UHFFFAOYSA-N 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- 230000002147 killing effect Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000004020 luminiscence type Methods 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 2
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 2
- LFSXCDWNBUNEEM-UHFFFAOYSA-N phthalazine Chemical compound C1=NN=CC2=CC=CC=C21 LFSXCDWNBUNEEM-UHFFFAOYSA-N 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 239000002157 polynucleotide Substances 0.000 description 2
- 102000040430 polynucleotide Human genes 0.000 description 2
- 108091033319 polynucleotide Proteins 0.000 description 2
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 2
- 125000001453 quaternary ammonium group Chemical group 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- 150000003290 ribose derivatives Chemical group 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 239000012265 solid product Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000003765 sweetening agent Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 150000003852 triazoles Chemical class 0.000 description 2
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 2
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- JUDOLRSMWHVKGX-UHFFFAOYSA-N 1,1-dioxo-1$l^{6},2-benzodithiol-3-one Chemical compound C1=CC=C2C(=O)SS(=O)(=O)C2=C1 JUDOLRSMWHVKGX-UHFFFAOYSA-N 0.000 description 1
- MBIZXFATKUQOOA-UHFFFAOYSA-N 1,3,4-thiadiazole Chemical compound C1=NN=CS1 MBIZXFATKUQOOA-UHFFFAOYSA-N 0.000 description 1
- WJFKNYWRSNBZNX-UHFFFAOYSA-N 10H-phenothiazine Chemical compound C1=CC=C2NC3=CC=CC=C3SC2=C1 WJFKNYWRSNBZNX-UHFFFAOYSA-N 0.000 description 1
- TZMSYXZUNZXBOL-UHFFFAOYSA-N 10H-phenoxazine Chemical compound C1=CC=C2NC3=CC=CC=C3OC2=C1 TZMSYXZUNZXBOL-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- VEPOHXYIFQMVHW-XOZOLZJESA-N 2,3-dihydroxybutanedioic acid (2S,3S)-3,4-dimethyl-2-phenylmorpholine Chemical compound OC(C(O)C(O)=O)C(O)=O.C[C@H]1[C@@H](OCCN1C)c1ccccc1 VEPOHXYIFQMVHW-XOZOLZJESA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 241000759909 Camptotheca Species 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 230000005778 DNA damage Effects 0.000 description 1
- 231100000277 DNA damage Toxicity 0.000 description 1
- 230000004543 DNA replication Effects 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 208000030453 Drug-Related Side Effects and Adverse reaction Diseases 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 102000008100 Human Serum Albumin Human genes 0.000 description 1
- 108091006905 Human Serum Albumin Proteins 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- WRYCSMQKUKOKBP-UHFFFAOYSA-N Imidazolidine Chemical compound C1CNCN1 WRYCSMQKUKOKBP-UHFFFAOYSA-N 0.000 description 1
- 229930194542 Keto Natural products 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 244000246386 Mentha pulegium Species 0.000 description 1
- 235000016257 Mentha pulegium Nutrition 0.000 description 1
- 235000004357 Mentha x piperita Nutrition 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 150000001204 N-oxides Chemical class 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical group C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 1
- 208000015634 Rectal Neoplasms Diseases 0.000 description 1
- 230000018199 S phase Effects 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 101710183280 Topoisomerase Proteins 0.000 description 1
- 206010070863 Toxicity to various agents Diseases 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 description 1
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 125000006598 aminocarbonylamino group Chemical group 0.000 description 1
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 1
- 229940124339 anthelmintic agent Drugs 0.000 description 1
- 239000000921 anthelmintic agent Substances 0.000 description 1
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 1
- 239000002259 anti human immunodeficiency virus agent Substances 0.000 description 1
- 229940124411 anti-hiv antiviral agent Drugs 0.000 description 1
- 230000000719 anti-leukaemic effect Effects 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 229940100197 antimetabolite Drugs 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 125000005110 aryl thio group Chemical group 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- DRTQHJPVMGBUCF-PSQAKQOGSA-N beta-L-uridine Natural products O[C@H]1[C@@H](O)[C@H](CO)O[C@@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-PSQAKQOGSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 230000005907 cancer growth Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 125000004181 carboxyalkyl group Chemical group 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 238000012054 celltiter-glo Methods 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229940112822 chewing gum Drugs 0.000 description 1
- 235000015218 chewing gum Nutrition 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000013611 chromosomal DNA Substances 0.000 description 1
- WCZVZNOTHYJIEI-UHFFFAOYSA-N cinnoline Chemical compound N1=NC=CC2=CC=CC=C21 WCZVZNOTHYJIEI-UHFFFAOYSA-N 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013256 coordination polymer Substances 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000000392 cycloalkenyl group Chemical group 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 231100000409 cytocidal Toxicity 0.000 description 1
- 230000000445 cytocidal effect Effects 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 239000005549 deoxyribonucleoside Substances 0.000 description 1
- 238000011033 desalting Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 125000004655 dihydropyridinyl group Chemical group N1(CC=CC=C1)* 0.000 description 1
- 230000003292 diminished effect Effects 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 230000005782 double-strand break Effects 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000010685 fatty oil Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 229940014259 gelatin Drugs 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229930182478 glucoside Natural products 0.000 description 1
- 150000008131 glucosides Chemical class 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 125000005553 heteroaryloxy group Chemical group 0.000 description 1
- 125000005368 heteroarylthio group Chemical group 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 235000001050 hortel pimenta Nutrition 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 125000002349 hydroxyamino group Chemical group [H]ON([H])[*] 0.000 description 1
- MTNDZQHUAFNZQY-UHFFFAOYSA-N imidazoline Chemical compound C1CN=CN1 MTNDZQHUAFNZQY-UHFFFAOYSA-N 0.000 description 1
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000002537 isoquinolines Chemical class 0.000 description 1
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- XMGQYMWWDOXHJM-UHFFFAOYSA-N limonene Chemical compound CC(=C)C1CCC(C)=CC1 XMGQYMWWDOXHJM-UHFFFAOYSA-N 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 238000003670 luciferase enzyme activity assay Methods 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000007102 metabolic function Effects 0.000 description 1
- 230000037323 metabolic rate Effects 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229960001047 methyl salicylate Drugs 0.000 description 1
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000000116 mitigating effect Effects 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000007524 negative regulation of DNA replication Effects 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000000346 nonvolatile oil Substances 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 239000007968 orange flavor Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 150000002972 pentoses Chemical group 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229950000688 phenothiazine Drugs 0.000 description 1
- 150000008300 phosphoramidites Chemical class 0.000 description 1
- 125000004437 phosphorous atom Chemical group 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- CPNGPNLZQNNVQM-UHFFFAOYSA-N pteridine Chemical compound N1=CN=CC2=NC=CN=C21 CPNGPNLZQNNVQM-UHFFFAOYSA-N 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical group OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 1
- ILVXOBCQQYKLDS-UHFFFAOYSA-N pyridine N-oxide Chemical class [O-][N+]1=CC=CC=C1 ILVXOBCQQYKLDS-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- LJPZHJUSICYOIX-UHFFFAOYSA-N quinolizidine Chemical compound C1CCCC2CCCCN21 LJPZHJUSICYOIX-UHFFFAOYSA-N 0.000 description 1
- 238000009790 rate-determining step (RDS) Methods 0.000 description 1
- 230000006798 recombination Effects 0.000 description 1
- 238000005215 recombination Methods 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 239000002342 ribonucleoside Substances 0.000 description 1
- 125000000548 ribosyl group Chemical group C1([C@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 238000004062 sedimentation Methods 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 1
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 239000012929 tonicity agent Substances 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- DRTQHJPVMGBUCF-UHFFFAOYSA-N uracil arabinoside Natural products OC1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-UHFFFAOYSA-N 0.000 description 1
- 229940045145 uridine Drugs 0.000 description 1
- 231100000925 very toxic Toxicity 0.000 description 1
- 235000012431 wafers Nutrition 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/26—Acyclic or carbocyclic radicals, substituted by hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H11/00—Compounds containing saccharide radicals esterified by inorganic acids; Metal salts thereof
- C07H11/04—Phosphates; Phosphites; Polyphosphates
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
- C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
- C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
- C07H19/207—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids the phosphoric or polyphosphoric acids being esterified by a further hydroxylic compound, e.g. flavine adenine dinucleotide or nicotinamide-adenine dinucleotide
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Engineering & Computer Science (AREA)
- Biotechnology (AREA)
- Genetics & Genomics (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
Description
式中、Mは、ヒドロキシルまたはチオールを表し、R1は、H、C1〜C4アシル、または酵素反応部を表し;
R2およびR3は、同一である、または異なっており、独立に、水素、ハロ、ヒドロキシル、アルコキシ、または酵素反応部を表し;
Bは、水素、置換もしくは非置換チミン、置換もしくは非置換アデニン、置換もしくは非置換シトシン、置換もしくは非置換グアニン、置換もしくは非置換ウラシル、5−フルオロウラシル、5−アザシトシン、2−フルオロアデニン、または2−クロロアデニンである;あるいは
Bは、アデニン、チミン、シトシンまたはグアニン以外のヘテロアリール基またはヘテロ脂環式基であり、好ましくは1〜3個の単環式環および1〜3個のN、OもしくはS原子を有する。
式中、Mはヒドロキシルまたはチオールを表し、Aはヌクレオシドまたはその類似体を表す。
式中、Mはヒドロキシルまたはチオール、好ましくはヒドロキシルを表し、R1はH、C1〜C4アシル、好ましくはアセチル、任意選択により置換されたポリヌクレオチド、好ましくは、任意選択により置換されたポリジヌクレオチド、または酵素反応(特に、開裂可能)部、例えば−RCOOR’および−NHCOR(式中、RおよびR’はC1〜C4アルキルまたはアルケニル、例えばC2もしくはC3アルケニルである)を表し;
R2およびR3は、同一でも異なっていてもよく、独立に水素、ハロゲン、ヒドロキシル、アルコキシル、または酵素的に反応性な(特に、開裂可能な)部分(例えば、アセチル)によって保護されているヒドロキシル基を表し;
Bは、チミン、アデニン、シトシン、グアニン、ウラシル、5−フルオロウラシル、5−アザシトシン、2−フルオロアデニン、2−クロロアデニン、水素、任意選択により置換されたチミン、任意選択により置換されたアデニン、任意選択により置換されたシトシン、または任意選択により置換されたグアニンであり、本明細書における任意選択の置換基は、好ましくは、アルキル、アリール、またはヘテロアリールもしくはヘテロ脂環式基であり、該ヘテロアリールまたはヘテロ脂環式基は、好ましくは、1〜3個の単環式環または縮合環を有し、各環の中に1〜3個のN、OまたはS原子を含む。別法として、または代替の実施形態において、Bは、1〜3個の単環式環および1〜3個のN、OまたはS原子を有するが、アデニン、チミン、シトシンまたはグアニン以外のヘテロアリールまたはヘテロ脂環式基である。式Iおよび式IIにおいて、A部分のアミノおよびヒドロキシは、当技術分野で知られている保護基によって保護することができる。好ましいアミノ保護基としては、アセチル、ベンゾイル、イソブチリル、tert−ブチルオキシカルボニル、ホルミル、ベンジル、p−メトキシベンジルオキシカルボニル、トリチルなどが挙げられる。好ましいヒドロキシ保護基としては、アセチル、トルフルオロアセチル、ピバロイル、ベンゾイル、アルキルカルボニル、アルキル、メチル、メトキシメチル、ベンジルオキシメチル、ベンジル、トリメチルシリル、t−ブチルジメチルシリルなどが挙げられる。当業者に知られているその他の好適な保護基は、その開示が本明細書に参照によって組み込まれるGreene、T.、Wuts、P.G.M.、Protective Groups in Organic Synthesis、Wiley(1999)に開示されている。ヒドロキシルおよびアミノに好ましい保護基としては、アミド、エステルなど、酵素反応(特に、開裂可能)部が挙げられる。
(1)PCl3をRHのアゾールと反応させ、式IVのホスフィントリアミン反応物を生成する:
である。
(2)式IVのホスフィントリアミン反応物をCPTと反応させて、式VのCPT 20(S)−O−ホスホルアミダイトモノエステル中間体を生成する:
(3)式VのCPT 20(S)−O−ホスホルアミダイトモノエステル中間体を、好適に保護された式IIIの化合物と反応させ、式VIの20(S)−O−ホスホルアミダイトジエステル前駆体を生成する:
式中、R1、R2、R3およびR4は、前記の通りであり、R1はHであり、これはスキーム1の合成プロセス間で式IIIの化合物と反応させる前に好適な保護基で置換され、R2またはR3はヒドロキシであり、前記ヒドロキシはスキーム1の合成プロセス間で式IIIの化合物と反応させる前に保護基で保護されており、Bはアミノを含み、アミノは、スキーム1の合成プロセス間で式IIIの化合物と反応させる前に保護基で保護される。
(4)式VIの20(S)−O−ホスホルアミダイトジエステル前駆体を加水分解した後、酸化およびアンモノリシスによって保護基を除去して、式IIのCPT 20(S)−O−ヌクレオチドCPT誘導体を生成する。
(5)式IIの化合物を塩基と反応させることによって、前記化合物を対応する塩に転換し、対応する塩を得る。このステップで使用できる塩基としては、これらに限定されないが、NaOH、Na2CO3、NaHCO3、KOH、KHCO3、K2CO3、LiOH、LiHCO3、Li2CO3、NH4HCO3、Ca(OH)2、CaCO3、Ca(HCO3)2、Mg(HCO3)2、Zn(HCO3)2、Zn(OH)2、およびFe(OH)3が挙げられ、第四級アンモニウム塩が所望される場合、好適な第四級アンモニウム塩基が使用される。
(氷浴に入れてある)乾燥した100mL丸底フラスコの中に無水トリアゾール317.5mg(4.59mmol)、Arの保護下の新たに蒸留したピリジン20ml、および三塩化リン0.2ml(2.29mmol)を添加した。氷浴を取り外した後に次いで、室温で0.5時間撹拌し、20mLの新たに蒸留したピリジン中の無水CPT500mg(1.43mmolのCPT)を添加し、次いで室温で2時間撹拌し続けた。CPTを完全に消費または転換させた後、20mLの新たに蒸留したピリジン中の3’Bz−5−FdU 1.24g(3.60mmol)を添加し、混合液を0.5時間撹拌し続けた。前のステップで生成した物質を完全に消費した後、アルゴン保護を外し、5mLの0.4M I2/THF溶液を添加した。反応は約1分のうちに完了し、溶液は赤紫色に変化した。溶媒を減圧蒸留法により除去し、黄色の固形生成物を得、次いでこれを5mLの濃縮アンモニアに溶解し、黄褐色の溶液を生成した。溶液を60℃で3時間撹拌して鮮やかな黄色に変化させ、その後、大部分の溶媒を減圧蒸留法により除去し、次いで、逆相カラムに通した。採集される標的溶離液を集め、大部分の溶媒を減圧蒸留法によって除去した後、希釈HCl溶液でpHを1に調節し、15mLのジクロロメタンで3回抽出した。抽出液からの有機相を採集し、一緒に組み合わせた。組み合わせた有機相を水で抽出し、抽出液からの水相を採集し濃縮した。濃縮した水相を逆相カラムに通し、やや黄色で固形の標的生成物420mg(0.64mmole)を生成し、TLCおよびNMRの結果は、該生成物が90%を超える純度でCPT 20(S)−ヌクレオチドを含んでいたことを示した。ES−MS(陰性検出モード):C29H25FN4O11P(655)、found 655。1H NMR (400MHz, D2O): δ 9.195(s, 1H), 8.567(s, 1H), 8.377-8.308(d, 1H), 8.207(s, 1H), 8.107-8.094(d, 1H), 7.954-7.887(t, 1H), 7.690-7.584(t, 1H), 7.524(s, 1H), 5.742-5.691 (m, 1H), 5.521-5.418(m, 2H), 4.665-4.618(d, 1H), 4.493-4.445(d, 1H), 4.370(s, 1H), 3.959-3.915(m, 2H), 3.800 (s, 1H), 2.386-2.289(m, 2H), 2.221-2.014(m, 2H), 1.064-1.027(t, 3H), 13C : δ 172.228, 159.579, 158.645, 151.554, 150.864, 148.157, 147.211, 145.426, 140.157, 131.415, 129.875, 128.754, 128.542, 128.225, 127.660, 126.547, 120.519, 110.875, 105.512, 99.588, 85.645, 85.245, 77.514, 71.655, 67.251, 50.255, 39.224, 11.245, 7.241. 31P: δ -2.324。
化合物Dix−905(化合物905とも呼ばれる)のがん細胞を死滅させる能力を測定するために、本発明者らは、様々な細胞株を用いて、Cell Titer−Gloキット(Promega)による細胞の生死判別試験を実施した。キットは、酵素的ルシフェラーゼアッセイによってATPレベルを測定する。正常な新陳代謝率を有し、正常なレベルのATPを生成する生存細胞は、ルシフェラーゼ基質の代謝回転率が高く、これは酵素反応のためにATPを要し、発光シグナルを発する。一方、死んでいく細胞は、その代謝機能が減退しているため、発光シグナルをあまり出さない。発した発光シグナルは、次いで照度計によって捕獲されることになる。
図1 Dix−905は、H1693細胞において、CPTよりも良好に殺細胞反応を引き起こした。
図2 Dix−905処理は、H1693において、相乗効果のために、CPT、フロクシウリジン、およびエトポシドよりも効果的に殺細胞をもたらした。
図3 Dix−905は、H1693において、カスパーゼ活性(アポトーシス経路)を介して、時間および用量に依存的な細胞死を導いた。
図4 Dix−905は、H146において、CPよりも良好に殺細胞反応を導いた。
図5 Dix−905は、H146において、CPT、フロクシウリジン、およびエトポシドよりも効果的に殺細胞を引き起こした。
図6 Dix−905は、H146において、カスパーゼ活性(アポトーシス経路)を介して、時間および用量に依存的な細胞死を導いた。
図7 Dix−905は、HCT116結腸細胞において、CPT、5−FUおよびエトポシドよりも殺細胞に効果的だった。
図8 HCT116細胞におけるDix−905およびCPTによる用量依存的な細胞死。
実施例1の手順を使用することによって、Dix−902、Dix−904およびDix−906の抗がん活性を測定し、試験結果を表3、4および5にそれぞれまとめた。
Claims (17)
- 式IIの化学構造
(式中、R1が水素、C1〜C4アシルを表し、
R2およびR3が、同一である、または異なっており、独立に、水素、ハロ、ヒドロキシル、またはアルコキシ基を表し、
Bは、任意選択により置換されたチミン、任意選択により置換されたアデニン、任意選択により置換されたシトシン、任意選択により置換されたグアニン、任意選択により置換されたウラシル、5−フルオロウラシル、5−アザシトシン、2−フルオロアデニン、2−クロロアデニン、または3,4,7,8−テトラヒドロイミダゾ[1,3]−ジアゼピン−8−オールである、あるいは
Bは、アデニン、チミン、シトシンまたはグアニン以外のヘテロ芳香族またはヘテロ脂環式基である)
を有する、請求項1に記載のカンプトテシン誘導体。 - Bは、アデニン、チミン、シトシンまたはグアニン以外のヘテロ芳香族またはヘテロ脂環式基であり、1〜3個の単環式環または縮合環および1〜3個のN、OまたはS原子を有する、請求項2に記載のカンプトテシン誘導体。
- Bが、置換チミン、置換アデニン、置換ウラシル、置換シトシン、または置換グアニンであり、置換基が、アルキル、アリール、ヘテロアリールまたはヘテロ脂環式基であり、ヘテロアリールまたはヘテロ脂環式基が、1〜3個の単環式環または縮合環および1〜3個のN、OまたはS原子を含む、請求項2に記載のカンプトテシン誘導体。
- R1がC1〜C4アシルである、請求項2に記載のカンプトテシン誘導体。
- R1がアセチルである、請求項5に記載のカンプトテシン誘導体。
- R1=R3=H、R2=OH、B=チミン、アデニン、シトシン、グアニン、ウラシル、または5−アザシトシンである、請求項2に記載のカンプトテシン誘導体。
- R1=Ac、R2=R3=H、B=チミン、アデニン、シトシン、グアニン、ウラシル、5−アザシトシン、または2−クロロアデニンであって、アミノ基の水素1個がアセチル基で置換されている、請求項2に記載のカンプトテシン誘導体。
- R1=Ac、R2=F、R3=H、B=2−クロロアデニンであって、アミノ基の水素1個がアセチルで置換されている、請求項2に記載のカンプトテシン誘導体。
- R1=Ac、R2=H、R3=OAc、B=2−フルオロアデニンであって、アミノ基の水素1個がアセチルで置換されている、請求項2に記載のカンプトテシン誘導体。
- R1=Ac、R3=H、R2=OAc、B=チミン、アデニン、シトシン、グアニン、ウラシル、5−アザシトシンであって、アミノ基の水素1個がアセチルで置換されている、請求項2に記載のカンプトテシン誘導体。
- 以下のステップ:
(1)PCl3をRHのアゾールと反応させて、式IVのホスフィントリアミン反応物を生成するステップ、
である。
(2)式IVのホスフィントリアミン反応物をCPTと反応させて、式VのCPT−20(S)−O−ホスホルアミダイトモノエステル中間体を生成するステップ、
(3)式VのCPT 20(S)−O−ホスホルアミダイト中間体を、式IIIの好適に保護された化合物と反応させて、式VIの20(S)−O−ホスホルアミダイトジエステル前駆体を生成するステップ
(式中、
R1は、H、またはC1〜C4アシルを表し、R1はHであり、Hは、式IIIの化合物と反応する前に、好適な保護基で置換されており、
R2およびR3は、同一である、または異なっており、それぞれが、水素、ハロ、ヒドロキシル、またはアルコキシを表し、R2またはR3は、ヒドロキシルであり、ヒドロキシル基は、式IIIの化合物と反応する前に、適切に保護されており、
Bは、任意選択により置換されたチミン、任意選択により置換されたアデニン、任意選択により置換されたシトシン、任意選択により置換されたグアニン、任意選択により置換されたウラシル、5−フルオロウラシル、5−アザシトシン、2−フルオロアデニン、2−クロロアデニンまたは3,4,7,8−テトラヒドロイミダゾ[1,3]ジアゼピン−8−オールである、あるいは
Bは、アデニン、チミン、シトシンまたはグアニン以外のヘテロ芳香族またはヘテロ脂環式基であり、1〜3個の単環または縮合環および1〜3個のN、OまたはS原子を有しており、
Bは、アミノを含み、アミノ基は、式IIIの化合物と反応する前に、適切に保護されている)、
(4)式VIの20(S)−O−ホスホルアミダイトジエステル前駆体を加水分解した後、酸化およびアンモノリシスを経て保護基を外し、式IIのCPT 20(S)−O−ヌクレオチドCPT誘導体を生成するステップ、ならびに
(5)任意選択により、式IIの化合物を、対応する塩に転換するステップ
を含む、請求項2に記載の化合物を調製する方法。 - 請求項1から12のいずれか一項の少なくとも1種のカンプトテシン誘導体および薬学的に許容される担体または希釈液を含む、医薬製剤。
- がんが、肺がん、乳がん、結腸がん、前立腺がん、メラノーマ、膵臓がん、胃がん、肝臓がん、脳腫瘍、腎臓がん、子宮がん、頸がん、卵巣がん、尿路がん、消化管がん、白血病、小細胞性肺がん、固形腫瘍または血液感染性の腫瘍であり、前記がんの治療用の医薬の調製における請求項14に記載の製剤の使用方法。
- 前記がんが小細胞性肺がんである、請求項15に記載の方法。
- 前記がんが結腸がんである、請求項15に記載の方法。
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/CN2011/077705 WO2013013404A1 (zh) | 2011-07-27 | 2011-07-27 | 水溶性喜树碱衍生物、药物组合物及其用途 |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2014521610A JP2014521610A (ja) | 2014-08-28 |
JP5826933B2 true JP5826933B2 (ja) | 2015-12-02 |
Family
ID=47600478
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2014521901A Expired - Fee Related JP5826933B2 (ja) | 2011-07-27 | 2011-07-27 | 水溶性カンプトテシン誘導体、医薬組成物およびそれらの使用 |
Country Status (5)
Country | Link |
---|---|
US (1) | US9334299B2 (ja) |
EP (1) | EP2738176B1 (ja) |
JP (1) | JP5826933B2 (ja) |
BR (1) | BR112014001959A2 (ja) |
WO (1) | WO2013013404A1 (ja) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104193790A (zh) * | 2014-09-25 | 2014-12-10 | 王庚禹 | 一种甲酰腺嘌呤化合物 |
CN105131039B (zh) * | 2015-09-18 | 2017-09-15 | 东南大学 | 一种喜树碱类磷脂化合物、其药物组合物及应用 |
WO2022013393A1 (en) * | 2020-07-16 | 2022-01-20 | Aarhus Universitet | Phosphoramidite synthesis on-demand |
CN112704683A (zh) * | 2020-12-30 | 2021-04-27 | 烟台大学 | 一种新型喜树碱衍生物及其制备抗肿瘤药物的应用 |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007052308A2 (en) * | 2005-11-03 | 2007-05-10 | Brain N' Beyond Biotech Pvt. Ltd. | Glyco-phosphorylated biologically active agents |
CN102153607B (zh) * | 2010-02-11 | 2015-07-15 | 湖南方盛华美医药科技有限公司 | 水溶性喜树碱衍生物及包含其的药物组合物 |
-
2011
- 2011-07-27 BR BR112014001959A patent/BR112014001959A2/pt not_active IP Right Cessation
- 2011-07-27 EP EP11869903.2A patent/EP2738176B1/en not_active Not-in-force
- 2011-07-27 JP JP2014521901A patent/JP5826933B2/ja not_active Expired - Fee Related
- 2011-07-27 WO PCT/CN2011/077705 patent/WO2013013404A1/zh active Application Filing
- 2011-07-27 US US14/235,158 patent/US9334299B2/en not_active Expired - Fee Related
Also Published As
Publication number | Publication date |
---|---|
EP2738176A4 (en) | 2015-03-04 |
EP2738176B1 (en) | 2016-11-16 |
BR112014001959A2 (pt) | 2017-02-21 |
US9334299B2 (en) | 2016-05-10 |
EP2738176A1 (en) | 2014-06-04 |
WO2013013404A1 (zh) | 2013-01-31 |
JP2014521610A (ja) | 2014-08-28 |
US20140155336A1 (en) | 2014-06-05 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
KR100829875B1 (ko) | 항암제로서의 병용 의약 조성물 | |
CN109553651B (zh) | 4’-硫代核苷的新型化合物及其制备方法、药物组合物和应用 | |
US20040002596A1 (en) | Nucleoside compounds and uses thereof | |
JP2004505889A (ja) | ヌクレオシド化合物およびその使用 | |
JP5890043B2 (ja) | 抗癌活性を有する2−デオキシ単糖の新規なアセテート | |
JP5826933B2 (ja) | 水溶性カンプトテシン誘導体、医薬組成物およびそれらの使用 | |
AU2007293377A1 (en) | L- OddC prodrugs for cancer | |
CN101787064B (zh) | 阿糖胞苷衍生物及其在抗癌抗肿瘤中的用途 | |
CN102924507A (zh) | 一种抗肿瘤化合物及其制备方法与应用、药物组合物 | |
CN102153607B (zh) | 水溶性喜树碱衍生物及包含其的药物组合物 | |
WO2016130271A1 (en) | Substituted pyrrolo[2,3-d]pyrimidines for selectively targeting tumor cells with fr-alpha and fr-beta type receptors | |
AU2012276175B2 (en) | Camptothecin derivative, method for preparing same, pharmaceutical composition and use thereof | |
US20230295163A1 (en) | Tetracyclic derivative, method for preparing same and use thereof in medicine | |
WO2020154742A1 (en) | Inhibitors of the enzyme enolase for precision oncology | |
TWI382978B (zh) | 化學化合物 | |
CN116096372A (zh) | 一种egfr抑制剂、其制备方法和在药学上的应用 | |
RU2299212C2 (ru) | Гексациклические соединения, фармацевтическая композиция, содержащая их и их применение в качестве противоопухолевых средств, способ получения гексациклических соединений | |
CN101787066B (zh) | 阿糖胞苷衍生物及其在抗癌抗肿瘤中的用途 | |
JP2004505899A (ja) | 5’−デオキシ−n−(置換されたオキシカルボニル)−5−フルオロシトシン及びその誘導体、その製造方法、並びに、これを有効性分として含む抗癌剤組成物 | |
JP2767176B2 (ja) | 抗癌剤 | |
WO2011113175A1 (zh) | 阿糖胞苷前药衍生物及其在抗癌抗肿瘤中的用途 | |
JP4768909B2 (ja) | トポイソメラーゼ阻害剤 | |
EP2854864B1 (en) | Compositions comprising oligomers of gemcitabine for use in therapy | |
WO2011113174A1 (zh) | 阿糖胞苷衍生物及其在抗癌抗肿瘤中的用途 | |
ES2594499A1 (es) | Complejos de Rutenio para el tratamiento del cáncer |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20150217 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20150507 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20150616 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20150821 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20150915 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20151014 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 5826933 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
LAPS | Cancellation because of no payment of annual fees |